Autoantibodies in diseases such as SLE and MS arise by clonal expansion of a few B cells. These clones diversify by somatic mutation and V gene rearrangement to develop B cells that secrete pathogenic autoantibodies. It is important to know the specificity of the B cells that initiate clonal expansion and the detailed mechanism(s) by which they evolve into high affinity autoantibodies. We will determine these properties by analysis of the receptors of B cell subsets that may contribute to the precursor pool. We will then study the evolution of autoantibody by studying autoantibody clones derived from germinal centers of mice as they develop induced and spontaneous autoimmunity. Based on this information we will construct transgenic mice with the genes coding for the antibody receptors on the B cells that initiate autoantibody production. These transgenics will allow us to study the regulation of these B cells and whether their regulation fails in autoimmune mice. We have preliminary evidence suggesting that Lupus-susceptible mice have an over-representation of the precursors of pathogenic autoantibodies in their naTve B cell pool. Therefore, this repertoire bias may represent a risk factor in Lupus-prone individuals. We will extend these repertoire analyses using microarrays that define the antibody repertoire of an individual and apply the analysis to mouse and humans with autoimmune diseases. We hope to discover patterns of V gene usage that distinguish autoimmune and disease-free individuals. These differences may contribute to understanding the origins and progression of autoimmunity and may eventually influence disease management.